The goal of this research is to understand how the physico-chemical properties of liposomes affect their use as drug carriers. Two significant physiological constraints limit the use of injectable particulate drug carriers: removal of the carrier by cells of reticuloendothelial system (RES) and internalization of the carrier into the lysosomal apparatus where it is subject to degradation. Prolongation of the circulatory life time of large liposomes would enhance their utility as sustained release vehicles and permit site-directing of the carrier to vascular targets. Success in introducing molecules directly into the cytoplasm could ultimately result in more effective therapy for viral diseases, such as hepatitis or to a technique for gene replacement therapy in vivo. Modifications of the surface of the carrier by hydrophilic polymers will be studied as a means of circumventing its recognition and uptake by cells of the RES. Modified carriers will be prepared from both liposomes and latex microspheres and characterized in detail. The interaction and uptake of such modified carriers by Kupffer cells will be studied in cell culture. Quantitation of uptake will be examined as a function of the type of surface modification, carrier composition, carrier size, and dose. Experiments with the modified carriers will quantitate the pharmacokinetics, disposition, and availability of the carrier and its contents in vivo in a systematic fashion. To induce cytoplasmic delivery of liposome encapsulated agents, pH sensitive lipid compositions will be optimized for in vivo use. This concept is based on the fact that many enveloped viruses deliver their genome into cells following endocytosis and a subsequent pH triggered conformational change of the viral membrane protein. This conformational change results in fusion of the viral envelope with the endosomal membrane. The liposomal parameters (composition, size and presence of pH sensitive trigger lipids) that influence the rate and extent of delivery of the liposome contents as well as the intracellular location of the delivered compounds will be studied in vivo by a sensitive double label technique.